Denosumab is a human monoclonal IgG2 antibody produced in a mammalian cell line (CHO) by recombinant DNA technology.

Excipient with known effect:

Each ml of solution contains 47 mg sorbitol (E420) (see section 4.4).

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Solution for injection (injection).

Clear, colourless to slightly yellow solution.

4. Clinical particulars

4.1 Therapeutic indications

Treatment of osteoporosis in postmenopausal women and in men at increased risk of fractures. In postmenopausal women Prolia significantly reduces the risk of vertebral, non-vertebral and hip fractures.

Treatment of bone loss associated with hormone ablation in men with prostate cancer at increased risk of fractures (see section 5.1). In men with prostate cancer receiving hormone ablation, Prolia significantly reduces the risk of vertebral fractures.

4.2 Posology and method of administration

Posology

The recommended dose of Prolia is 60 mg administered as a single subcutaneous injection once every 6 months into the thigh, abdomen or upper arm.

Patients must be adequately supplemented with calcium and vitamin D (see section 4.4).

Patients with renal impairment

No dose adjustment is required in patients with renal impairment (see sections 4.4 for recommendations relating to monitoring of calcium).

Patients with hepatic impairment

The safety and efficacy of denosumab have not been studied in patients with hepatic impairment (see section 5.2).

Elderly Patients (age ≥ 65)

No dose adjustment is required in elderly patients.

Paediatric population

Prolia is not recommended in paediatric patients (age < 18) as the safety and efficacy of Prolia in these patients have not been established. Inhibition of RANK/RANK ligand (RANKL) in animal studies has been coupled to inhibition of bone growth and lack of tooth eruption (see also section 5.3).

Method of administration

For subcutaneous use.

Administration should be performed by an individual who has been adequately trained in injection techniques.

The instructions for use, handling and disposal are given in section 6.6.

4.3 Contraindications

- Hypocalcaemia (see section 4.4).

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Calcium and Vitamin D supplementation

Adequate intake of calcium and vitamin D is important in all patients.

Precautions for use

Hypocalcaemia

It is important to identify patients at risk for hypocalcaemia. Hypocalcaemia must be corrected by adequate intake of calcium and vitamin D before initiating therapy. Clinical monitoring of calcium levels is recommended before each dose and, in patients predisposed to hypocalcaemia within two weeks after the initial dose. If any patient presents with suspected symptoms of hypocalcaemia during treatment (see section 4.8 for symptoms) calcium levels should be measured. Patients should be encouraged to report symptoms indicative of hypocalcaemia.

In the post-marketing setting, severe symptomatic hypocalcaemia has been reported (see section 4.8), with most cases occurring in the first weeks of initiating therapy, but it can occur later.

Skin Infections

Patients receiving Prolia may develop skin infections (predominantly cellulitis) leading to hospitalisation (see section 4.8). Patients should be advised to seek prompt medical attention if they develop signs or symptoms of cellulitis.

Osteonecrosis of the Jaw (ONJ)

ONJ has been reported rarely in clinical studies and in the post marketing setting in patients receiving denosumab at a dose of 60 mg every 6 months for osteoporosis. ONJ has been reported commonly in clinical studies in patients with advanced cancer treated with denosumab at the studied dose of 120 mg administered monthly.

It is important to evaluate patients for risk factors for ONJ before starting treatment. A dental examination with appropriate preventive dentistry is recommended prior to treatment with Prolia in patients with concomitant risk factors.

All patients should be encouraged to maintain good oral hygiene, receive routine dental check-ups, and immediately report any oral symptoms such as dental mobility, pain or swelling during treatment with Prolia.

While on treatment, patients should avoid invasive dental procedures if possible. For patients who develop ONJ while on Prolia therapy, dental surgery may exacerbate the condition. The management plan of the individual patients who develop ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ. Temporary interruption of treatment should be considered until the condition resolves and contributing risk factors are mitigated where possible

Atypical fractures of the femur

Atypical femoral fractures have been reported in patients receiving Prolia (see section 4.8). Atypical femoral fractures may occur with little or no trauma in the subtrochanteric and diaphyseal regions of the femur. Specific radiographic findings characterize these events. Atypical femoral fractures have also been reported in patients with certain comorbid conditions (e.g. vitamin D deficiency, rheumatoid arthritis, hypophosphatasia) and with use of certain pharmaceutical agents (e.g. bisphosphonates, glucocorticoids, proton pump inhibitors). These events have also occurred without antiresorptive therapy. Similar fractures reported in association with bisphosphonates are often bilateral; therefore the contralateral femur should be examined in Prolia-treated patients who have sustained a femoral shaft fracture. Discontinuation of Prolia therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient based on an individual benefit risk assessment. During Prolia treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Patients presenting with such symptoms should be evaluated for an incomplete femoral fracture.

Patients being treated with Prolia should not be treated concomitantly with other denosumab-containing medicinal products (for prevention of skeletal related events in adults with bone metastases from solid tumours).

Renal impairment

Patients with severe renal impairment (creatinine clearance < 30 ml/min) or receiving dialysis are at greater risk of developing hypocalcaemia. The risks of developing hypocalcaemia and accompanying parathyroid hormone elevations increase with increasing degree of renal impairment. Adequate intake of calcium, vitamin D and regular monitoring of calcium is especially important in these patients, see above.

Dry natural rubber

The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions.

Warnings for Excipients

This medicinal product contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not use Prolia.

4.5 Interaction with other medicinal products and other forms of interaction

In an interaction study, Prolia did not affect the pharmacokinetics of midazolam, which is metabolized by cytochrome P450 3A4 (CYP3A4). This indicates that Prolia should not alter the pharmacokinetics of medicinal products metabolized by CYP3A4.

There are no clinical data on the co-administration of denosumab and hormone replacement therapy (oestrogen), however the potential for a pharmacodynamic interaction is considered to be low.

In postmenopausal women with osteoporosis the pharmacokinetics and pharmacodynamics of denosumab were not altered by previous alendronate therapy, based on data from a transition study (alendronate to denosumab).

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of Prolia in pregnant women. Reproductive toxicity was shown in a study of cynomolgus monkeys, dosed throughout pregnancy with denosumab at AUC exposures 119-fold higher than the human dose (see section 5.3).

Prolia is not recommended for use in pregnant women.

Women who become pregnant during Prolia treatment are encouraged to enrol in Amgen's pregnancy surveillance programme. Contact details are provided in section 6 of the package leaflet  Information for the user.

Breast-feeding

It is unknown whether denosumab is excreted in human milk. In genetically engineered mice in which RANKL has been turned off by gene removal (a knockout mouse), studies suggest absence of RANKL (the target of denosumab see section 5.1) during pregnancy may interfere with maturation of the mammary gland leading to impaired lactation post-partum (see section 5.3). A decision on whether to abstain from breast-feeding or to abstain from therapy with Prolia should be made, taking into account the benefit of breast-feeding to the newborn/infant and the benefit of Prolia therapy to the woman.

Women who are breast-feeding during Prolia treatment are encouraged to enrol in Amgen's lactation surveillance program. Contact details are provided in section 6 of the package leaflet  Information for the user.

Fertility

No data are available on the effect of denosumab on human fertility. Animal studies do not indicate direct or indirect harmful effects with respect to fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

Prolia has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

The overall safety profile of Prolia was similar in patients with osteoporosis and in breast or prostate cancer patients receiving hormone ablation in five Phase III placebo-controlled clinical trials.

The most common side effects with Prolia (seen in more than one patient in ten) are musculoskeletal pain and pain in the extremity. Uncommon cases of cellulitis; rare cases of hypocalcaemia, hypersensitivity, osteonecrosis of the jaw and atypical femoral fractures (see sections 4.4 and section 4.8 - description of selected adverse reactions) have been observed in patients taking Prolia.

The following convention has been used for the classification of the adverse reactions (see table 1): very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000) and very rare (< 1/10,000). Within each frequency grouping and system organ class, adverse reactions are presented in order of decreasing seriousness.

In a pooled analysis of data from all phase II and phase III placebo controlled studies, Influenza-like illness was reported with a crude incidence rate of 1.2% for denosumab and 0.7 % for placebo. Although this imbalance was identified via a pooled analysis, it was not identified via a stratified analysis.

Description of selected adverse reactions

Hypocalcaemia

In two phase III placebo-controlled clinical trials in postmenopausal women with osteoporosis, approximately 0.05% (2 out of 4,050) of patients had declines of serum calcium levels (less than 1.88 mmol/l) following Prolia administration. Declines of serum calcium levels (less than 1.88 mmol/l) were not reported in either the two phase III placebo-controlled clinical trials in patients receiving hormone ablation or the phase III placebo-controlled clinical trial in men with osteoporosis.

In the post-marketing setting, rare cases of severe symptomatic hypocalcaemia have been predominantly reported in patients at increased risk of hypocalcaemia receiving Prolia, with most cases occurring in the first weeks of initiating therapy. Examples of the clinical manifestations of severe symptomatic hypocalcaemia have included QT interval prolongation, tetany, seizures and altered mental status (see section 4.4). Symptoms of hypocalcaemia in denosumab clinical studies included paresthesias or muscle stiffness, twitching, spasms and muscle cramps.

Skin infections

In phase III placebo-controlled clinical trials, the overall incidence of skin infections was similar in the placebo and the Prolia groups in postmenopausal women with osteoporosis (placebo [1.2%, 50 out of 4,041] versus Prolia [1.5%, 59 out of 4,050]); in men with osteoporosis (placebo [0.8%, 1 out of 120] versus Prolia [0%, 0 out of 120]) and in breast or prostate cancer patients receiving hormone ablation (placebo [1.7%, 14 out of 845] versus Prolia [1.4%, 12 out of 860]). Skin infections leading to hospitalisation were reported in 0.1% (3 out of 4,041) of postmenopausal women with osteoporosis receiving placebo versus 0.4% (16 out of 4,050) of women receiving Prolia. These cases were predominantly cellulitis. Skin infections reported as serious adverse reactions were similar in the placebo (0.6%, 5 out of 845) and the Prolia (0.6%, 5 out of 860) groups in the breast and prostate cancer studies.

In a single phase III placebo-controlled clinical trial in patients with prostate cancer receiving androgen deprivation therapy (ADT) an imbalance in cataract adverse events was observed (4.7% denosumab, 1.2% placebo). No imbalance was observed in postmenopausal women or men with osteoporosis or in women undergoing aromatase inhibitor therapy for nonmetastatic breast cancer.

Diverticulitis

In a single phase III placebo-controlled clinical trial in patients with prostate cancer receiving ADT an imbalance in diverticulitis adverse events was observed (1.2% denosumab, 0% placebo). The incidence of diverticulitis was comparable between treatment groups in postmenopausal women or men with osteoporosis and in women undergoing aromatase inhibitor therapy for nonmetastatic breast cancer.

Drug-related hypersensitivity reactions

In the post-marketing setting, rare events of drug-related hypersensitivity, including rash, urticaria, facial swelling, erythema, and anaphylactic reactions have been reported in patients receiving Prolia.

Musculoskeletal pain

Musculoskeletal pain, including severe cases, has been reported in patients receiving Prolia in the post-marketing setting. In clinical trials, musculoskeletal pain was very common in both denosumab and placebo groups. Musculoskeletal pain leading to discontinuation of study treatment was uncommon.

Other special populations

In clinical studies, patients with severe renal impairment (creatinine clearance < 30 ml/min) or receiving dialysis were at greater risk of developing hypocalcaemia in the absence of calcium supplementation. Adequate intake of calcium and vitamin D is important in patients with severe renal impairment or receiving dialysis (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie

4.9 Overdose

There is no experience with overdose in clinical studies. Denosumab has been administered in clinical studies using doses up to 180 mg every 4 weeks (cumulative doses up to 1,080 mg over 6 months), and no additional adverse reactions were observed.

Denosumab is a human monoclonal antibody (IgG2) that targets and binds with high affinity and specificity to RANKL, preventing activation of its receptor, RANK, on the surface of osteoclast precursors and osteoclasts. Prevention of the RANKL/RANK interaction inhibits osteoclast formation, function and survival, thereby decreasing bone resorption in cortical and trabecular bone.

Pharmacodynamic effects

Prolia treatment rapidly reduced the rate of bone turnover, reaching a nadir for the bone resorption marker serum type 1 C-telopeptides (CTX) (85% reduction) by 3 days, with reductions maintained over the dosing interval. At the end of each dosing interval, CTX reductions were partially attenuated from maximal reduction of ≥ 87% to approximately ≥ 45% (range 45-80%), reflecting the reversibility of Prolia's effects on bone remodelling once serum levels diminish. These effects were sustained with continued treatment. Bone turnover markers generally reached pre-treatment levels within 9 months after the last dose. Upon re-initiation, reductions in CTX by denosumab were similar to those observed in patients initiating primary denosumab treatment.

Immunogenicity

In clinical studies, neutralising antibodies have not been observed for Prolia. Using a sensitive immunoassay < 1% of patients treated with denosumab for up to 5 years tested positive for non neutralising binding antibodies with no evidence of altered pharmacokinetics, toxicity, or clinical response.

Treatment of osteoporosis in postmenopausal women

Efficacy and safety of Prolia administered once every 6 months for 3 years were investigated in post-menopausal women (7,808 women aged 60-91 years, of which 23.6% had prevalent vertebral fractures) with baseline bone mineral density (BMD) T-scores at the lumbar spine or total hip between 2.5 and 4.0 and a mean absolute 10-year fracture probability of 18.60% (deciles: 7.9-32.4%) for major osteoporotic fracture and 7.22% (deciles: 1.4-14.9%) for hip fracture. Women with other diseases or on therapies that may affect bone were excluded from this study. Women received calcium (at least 1,000 mg) and vitamin D (at least 400 IU) supplementation daily.

Prolia demonstrated a 40% relative reduction (0.5% absolute risk reduction) in the risk of hip fracture over 3 years (p < 0.05). The incidence of hip fracture was 1.2% in the placebo group compared to 0.7% in the Prolia group at 3 years.

The reduction in the incidence of new vertebral fractures, hip fractures and non-vertebral fractures by Prolia over 3 years were consistent regardless of the 10-year baseline fracture risk.

Effect on bone mineral density

Prolia significantly increased BMD at all clinical sites measured, versus placebo at 1, 2 and 3 years. Prolia increased BMD by 9.2% at the lumbar spine, 6.0% at the total hip, 4.8% at the femoral neck, 7.9% at the hip trochanter, 3.5% at the distal 1/3 radius and 4.1% at the total body over 3 years (all p < 0.0001).

In clinical studies examining the effects of discontinuation of Prolia, BMD returned to approximately pre-treatment levels and remained above placebo within 18 months of the last dose. These data indicate that continued treatment with Prolia is required to maintain the effect of the medicinal product. Re-initiation of Prolia resulted in gains in BMD similar to those when Prolia was first administered.

Open-label Extension Study in the Treatment of Postmenopausal Osteoporosis

A total of 4550 women (2343 Prolia & 2207 placebo) who missed no more than one dose of investigational product in the pivotal study described above and completed the month 36 study visit agreed to enrol in a 7-year, multinational, multicentre, open-label, single-arm extension study to evaluate the long-term safety and efficacy of Prolia. All women in the extension study received Prolia 60 mg every 6 months, as well as daily calcium (at least 1 g) and vitamin D (at least 400 IU). At month 60 of the extension study, after 8 years of Prolia treatment, the long-term group (n = 1542) had increased in BMD by 18.4% at the lumbar spine, 8.3% at the total hip, 7.8% at the femoral neck and 11.6% at the trochanter from the original pivotal study baseline. Fracture incidence was evaluated as a safety endpoint. In years 4 through 8, the rates of new vertebral and non-vertebral fractures did not increase over time; annualised rates were approximately 1.1% and 1.3% respectively.

Eight adjudicated cases of osteonecrosis of the jaw (ONJ) and two atypical fractures of the femur have occurred during the extension study.

Treatment of osteoporosis in men

Efficacy and safety of Prolia once every 6 months for 1 year were investigated in 242 men aged 31-84 years. Subjects with an eGFR < 30 ml/min/1.73 m2 were excluded from the study. All men received calcium (at least 1,000 mg) and vitamin D (at least 800 IU) supplementation daily.

Bone histology was evaluated in 62 postmenopausal women with osteoporosis or with low bone mass who were either naïve to osteoporosis therapies or had transitioned from previous alendronate therapy following 1-3 years treatment with Prolia. Forty-one women participated in the bone biopsy sub-study at month 24 of the extension study. Bone histology was also evaluated in 17 men with osteoporosis following 1 year treatment with Prolia. Bone biopsy results showed bone of normal architecture and quality with no evidence of mineralisation defects, woven bone or marrow fibrosis.

Treatment of bone loss associated with androgen deprivation

Efficacy and safety of Prolia once every 6 months for 3 years were investigated in men with histologically confirmed non-metastatic prostate cancer receiving ADT (1,468 men aged 48-97 years) who were at increased risk of fracture (defined as > 70 years, or < 70 years with a BMD T-score at the lumbar spine, total hip, or femoral neck < -1.0 or a history of an osteoporotic fracture.) All men received calcium (at least 1,000 mg) and vitamin D (at least 400 IU) supplementation daily.

Prolia significantly increased BMD at all clinical sites measured, relative to treatment with placebo at 3 years: 7.9% at the lumbar spine, 5.7% at the total hip, 4.9% at the femoral neck, 6.9% at the hip trochanter, 6.9% at the distal 1/3 radius and 4.7% at the total body (all p < 0.0001). In a prospectively planned exploratory analysis, significant increases in BMD were observed at the lumbar spine, total hip, femoral neck and the hip trochanter 1 month after the initial dose.

Efficacy and safety of Prolia once every 6 months for 2 years was investigated in women with non-metastatic breast cancer (252 women aged 35-84 years) and baseline BMD T-scores between -1.0 to -2.5 at the lumbar spine, total hip or femoral neck. All women received calcium (at least 1,000 mg) and vitamin D (at least 400 IU) supplementation daily.

The primary efficacy variable was percent change in lumbar spine BMD, fracture efficacy was not evaluated. Prolia significantly increased BMD at all clinical sites measured, relative to treatment with placebo at 2 years: 7.6% at lumbar spine, 4.7% at total hip, 3.6% at femoral neck, 5.9% at hip trochanter, 6.1% at distal 1/3 radius and 4.2% at total body (all p < 0.0001).

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Prolia in all subsets of the paediatric population in the treatment of bone loss associated with sex hormone ablative therapy, and in subsets of the paediatric population below the age of 2 in the treatment of osteoporosis. See section 4.2 for information on paediatric use.

5.2 Pharmacokinetic properties

Absorption

Following subcutaneous administration of a 1.0 mg/kg dose, which approximates the approved 60 mg dose, exposure based on AUC was 78% as compared to intravenous administration at the same dose level. For a 60 mg subcutaneous dose, maximum serum denosumab concentrations (Cmax) of 6 μg/ml (range 1-17 μg/ml) occurred in 10 days (range 2-28 days).

Biotransformation

Denosumab is composed solely of amino acids and carbohydrates as native immunoglobulin and is unlikely to be eliminated via hepatic metabolic mechanisms. Its metabolism and elimination are expected to follow the immunoglobulin clearance pathways, resulting in degradation to small peptides and individual amino acids.

Elimination

After Cmax, serum levels declined with a half-life of 26 days (range 6-52 days) over a period of 3 months (range 1.5-4.5 months). Fifty-three percent (53%) of patients had no measurable amounts of denosumab detected at 6 months post-dose.

No accumulation or change in denosumab pharmacokinetics with time was observed upon subcutaneous multiple-dosing of 60 mg once every 6 months. Denosumab pharmacokinetics was not affected by the formation of binding antibodies to denosumab and was similar in men and women. Age (28-87 years), race and disease state (low bone mass or osteoporosis; prostate or breast cancer) do not appear to significantly affect the pharmacokinetics of denosumab.

A trend was observed between higher body weight and lower exposure based on AUC and Cmax. However, the trend is not considered clinically important, since pharmacodynamic effects based on bone turnover markers and BMD increases were consistent across a wide range of body weight.

Linearity/non-linearity

In dose ranging studies, denosumab exhibited non-linear, dose-dependent pharmacokinetics, with lower clearance at higher doses or concentrations, but approximately dose-proportional increases in exposures for doses of 60 mg and greater.

Renal impairment

In a study of 55 patients with varying degrees of renal function, including patients on dialysis, the degree of renal impairment had no effect on the pharmacokinetics of denosumab.

Hepatic impairment

No specific study in patients with hepatic impairment was performed. In general, monoclonal antibodies are not eliminated via hepatic metabolic mechanisms. The pharmacokinetics of denosumab is not expected to be affected by hepatic impairment.

Paediatric population

The pharmacokinetic profile in paediatric populations has not been assessed.

5.3 Preclinical safety data

In single and repeated dose toxicity studies in cynomolgus monkeys, denosumab doses resulting in 100 to 150 times greater systemic exposure than the recommended human dose had no impact on cardiovascular physiology, male or female fertility, or produced specific target organ toxicity.

Standard tests to investigate the genotoxicity potential of denosumab have not been evaluated, since such tests are not relevant for this molecule. However, due to its character it is unlikely that denosumab has any potential for genotoxicity.

The carcinogenic potential of denosumab has not been evaluated in long-term animal studies.

In preclinical studies conducted in knockout mice lacking RANK or RANKL, impairment of lymph node formation was observed in the foetus. An absence of lactation due to inhibition of mammary gland maturation (lobulo-alveolar gland development during pregnancy) was also observed in knockout mice lacking RANK or RANKL.

In a study of cynomolgus monkeys dosed with denosumab during the period equivalent to the first trimester at AUC exposures up to 99-fold higher than the human dose (60 mg every 6 months), there was no evidence of maternal or foetal harm. In this study, foetal lymph nodes were not examined.

In another study of cynomolgus monkeys dosed with denosumab throughout pregnancy at AUC exposures 119-fold higher than the human dose (60 mg every 6 months), there were increased stillbirths and postnatal mortality; abnormal bone growth resulting in reduced bone strength, reduced haematopoiesis, and tooth malalignment; absence of peripheral lymph nodes; and decreased neonatal growth. A no observed adverse effect level for reproductive effects was not established. Following a 6 month period after birth, bone related changes showed recovery and there was no effect on tooth eruption. However, the effects on lymph nodes and tooth malalignment persisted, and minimal to moderate mineralisation in multiple tissues was seen in one animal (relation to treatment uncertain). There was no evidence of maternal harm prior to labour; adverse maternal effects occurred infrequently during labour. Maternal mammary gland development was normal.

In male mice genetically engineered to express huRANKL (knock-in mice), which were subjected to a transcortical fracture, denosumab delayed the removal of cartilage and remodelling of the fracture callus compared to control, but biomechanical strength was not adversely affected.

Knockout mice (see section 4.6) lacking RANK or RANKL exhibited decreased body weight, reduced bone growth and lack of tooth eruption. In neonatal rats, inhibition of RANKL (target of denosumab therapy) with high doses of a construct of osteoprotegerin bound to Fc (OPG-Fc) was associated with inhibition of bone growth and tooth eruption. These changes were partially reversible in this model when dosing with RANKL inhibitors was discontinued. Adolescent primates dosed with denosumab at 27 and 150 times (10 and 50 mg/kg dose) the clinical exposure had abnormal growth plates. Therefore, treatment with denosumab may impair bone growth in children with open growth plates and may inhibit eruption of dentition.

6. Pharmaceutical particulars

6.1 List of excipients

Acetic acid, glacial*

Sodium hydroxide (for pH adjustment)*

Sorbitol (E420)

Polysorbate 20

Water for injections

* Acetate buffer is formed by mixing acetic acid with sodium hydroxide

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

3 years.

Prolia may be stored at room temperature (up to 25°C) for up to 30 days in the original container. Once removed from the refrigerator, Prolia must be used within this 30 day period.

6.4 Special precautions for storage

Store in a refrigerator (2°C  8°C).

Do not freeze.

Keep the pre-filled syringe in the outer carton in order to protect from light.

6.5 Nature and contents of container

One ml solution in a single use pre-filled syringe made from type I glass with stainless steel 27 gauge needle, with or without needle guard.

The needle cover of the pre-filled syringe contains dry natural rubber, which is a derivative of latex (see section 4.4).

Pack size of one, presented in blistered (pre-filled syringe with or without a needle guard) or unblistered packaging (pre-filled syringe only).

6.6 Special precautions for disposal and other handling

Before administration, the solution should be inspected. Do not inject the solution if it contains particles, or is cloudy or discoloured. Do not shake excessively. To avoid discomfort at the site of injection, allow the pre-filled syringe to reach room temperature (up to 25°C) before injecting and inject slowly. Inject the entire contents of the pre-filled syringe. Dispose of any medicinal product remaining in the pre-filled syringe.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Amgen Europe B.V.

Minervum 7061

NL-4817 ZK Breda

The Netherlands

8. Marketing authorisation number(s)

EU/1/10/618/001

EU/1/10/618/002

EU/1/10/618/003

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 26 May 2010

Date of latest renewal: 15 January 2015

10. Date of revision of the text

January 2015

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu